A large and growing number of people suffer from diabetes mellitus and obesity. Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes and the disorder approaches epidemic proportions. Since the introduction of insulin in the 1920's, continuous efforts have been made to improve the treatment of diabetes mellitus.
The two conditions diabetes mellitus and obesity are related in the sense that diabetes is common among obese patients and vice versa. There is also a strong link between diabetes mellitus and obesity on one side and cardio-vascular diseases on the other. This leads to a shorter life span for people suffering from these conditions. It is well-known and documented that effective treatment of diabetes mellitus and obesity lead to fewer complications such as diabetic late-complications affecting e.g. vision and kidney function.
A number of treatment regimes are targeting excessive blood glucose whereas others are focused primarily on weight reduction. The most efficient anti-diabetic agent used to lower blood glucose is insulin and analog(s) thereof. It has been known for a long time that when traditional insulin is used to treat diabetes, it is associated with an increase in body weight. Insulin has to be injected subcutaneously up to several times per day.
Type 2 diabetes is generally treated in the early phases with diet and exercise. As the condition progresses, various oral anti-diabetic agents are added. Injected agents such as GLP-1 analogs may also be used at this stage. In general, these agents are most efficient in patients with functioning beta-cells capable of releasing insulin and amylin. In 95% of progressed type 2 diabetes patients' amylin precipitates in the pancreas and may constitute a cause of the final beta-cell failure (L. Yan, PNAS, 2006, 103(7), 2046-2051). Ultimately, the patient is no longer able to produce amylin and insulin. Like Type 1-diabetic patients, these progressed Type-2 diabetic patients are then treated with insulin in spite of the fact that the beta-cell actually produces two hormones amylin and insulin. Only very recently, it has become possible to substitute amylin as well as insulin.
Human amylin is a 37 amino acid long peptide which has physico-chemical properties that make its use as a drug troublesome. In particular, it has a tendency to fibrillate in-vitro and/or ex-vivo and become ineffective due to precipitation. A drug product called Symlin is currently on the market which contains an analog of human amylin (pramlintide) where three of the 37 amino acids are substituted to proline. This improves substantially the fibrillating tendency. However, even pramlintide is difficult to keep in solution at neutral pH and it is therefore provided in an acidic solution i.e. Symlin.
The actions of amylin in relation to diabetes and obesity are: Reduction of food intake leading to lower bodyweight, slower gastric emptying, smoothening of post-prandial glucose profiles, and a reduction in the excessive diabetic glucagon release (A. Young, Amylin: Physiology and Pharmacology, Academic Press (2005)). By and large the actions of amylin are mediated via identified CNS receptors rather than directly on the target organs.
Symlin is approved as an adjunct drug with insulin. Clinical trials have revealed improved HbA1c in the order of 0.3-0.6, a smoother and shallower post-prandial blood glucose profile and reduction in body weight in contrast to treatment with insulin alone. Symlin is currently administered as a separate injection at a separate injection site three times daily. If the patient also uses three insulin injections per day, this adds up to a total of six daily injections.
Symlin therapy is limited by nausea as a side-effect. The nausea is dose-related, but has a tendency to diminish with time. The pharmaco-kinetic profile of Symlin leads to rather large variations in plasma levels throughout the day. It takes approximately 20 minutes after a subcutaneous injection for Symlin to reach Cmax, and plasma t½ is in the order of 20-50 minutes (Colburn, W. A. J. Clin. Pharmacol. 36, 13-24 (1996). Ultimately, this leads to a need for three or more daily injections of Symlin in order to keep pharmacological plasma level without substantial side-effects. Even with three daily injections Symlin does not mimic the natural release profile of amylin very well. Amylin is released as meal related peaks with a duration close to 3-6 hours in contrast to the 1-1½ hour duration of an injected Symlin profile. Amylin also has a substantial basal level that is not mimicked by Symlin (A. Young, Amylin: Physiology and Pharmacology, Academic Press (2005)).
Type-1 diabetic patients are essentially without natural release of amylin and type-2 patients have lower levels than healthy individuals.
It would be useful to provide derivatives that have the activities of native human amylin, as well as derivatives which have a protracted PK-profile, show enhanced solubility and/or stability over native human amylin.